11-substituted-desa-pregnanes and derivatives thereof

ABSTRACT

This invention is directed to 11-substituted-desA-pregnanes and derivatives thereof which are useful as intermediates in the production of 9 Beta , 10 Alpha -known steroids of the pregnane series. These latter compounds can be utilized as progestational and salt-retaining agents.

United States Patent [191 Uskokovic et al.

11-SUBSTITUTED-DESA-PREGNANES AND DERIVATIVES THEREOF Inventors: Milan Radoje Uskokovic, Montclair;

Thomas Henry Williams, Cedar Grove, both of NJ.

Assignee: Hoffman-La Roche Inc., Nutley,

Filed: May 26, 1971 Appl. No.: 147,263

Related US. Application Data Division of Ser. No. 736,569, June 13, 1968, abandoned, which is a division of Ser. No. 499,094, Oct. 20, 1965, Pat. No. 3,574,761, which is a continuation-impart of Ser. No. 400,206, Sept. 29, 1964, Pat. No. 3,412,107.

US. Cl 260/456 R, 195/2, 260/338, 260/340.5, 260/340.7, 260/340.9, 260/343, 260/343.9, 260/345.9, 260/455 C, 260/456 P, 260/476 C, 260/485 L, 260/408 B, 260/586 R, 260/586 H, 424/278, 424/279, 424/283, 424/303, 424/308,'424/311, 424/331 260/3405, 340.7, 340.9, 345.9, 455 C, 476 C, 485 L, 488 B, 586 H [56] References Cited UNITED STATES PATENTS 3,412,107 11/1968 Uskokovic 260/340.9 3,574,761 4/1971 Uskokovic et a1 260/586 Primary Examiner-Joseph E. Evans Assistant Examiner-Gerald H. Schwartz Attorney, Agent, or Firm-Samuel L. Welt; Jon S. Saxe; Ronald A. Schapira 5 7] ABSTRACT This invention is directed to lll-substituted-desA- pregnanes and derivatives thereof which are useful as intermediates in the production of 9B, IOa-known steroids of the pregnane series. These latter compounds can be utilized as progestational and salt-retaining agents.

6 Claims, No Drawings II-SUBSTITUTED D-DESA-PREGNANES AND PEBlYIIXET RE RELATED APPLICATIONS DETAILED DESCRIPTION OF THE INVENTION This invention relates to novel chemical intermediates and processes useful in the preparation of steroids.

Natural steroids possess a 9a,l0,B-stereochemical configuration. Steroidal compounds possessing the unnatural 9,8,10a-configuration represent a pharmaceutically valuable class of compounds which, even though numerous members are known in the art, cannot be obtained by totally classified chemical means. In fact, the only known methods for obtaining steroids possessing the unnatural 9,3,10a-configuration involve at least one photochemical reaction. Such photochemical reactions involve irradiation with ultraviolet light of strong intensity for long periods of time and, in comparison with purely chemical reactions, are very inefficient and give only small yields.

It is an object of the present invention to provide intermediates and processes which enable the preparation of 90fl,lOa-steroids without the necessity of proceeding through a photochemical reaction. It is also an object of this invention to provide novel intermediates and processes which will enable the further exploration of steroids having the unnatural 9,8,l0a-configuration.

It is also an object of this invention to provide novel 9,3,10a-steroids.

The novel intermediates and processes of this invention are valuable and provide a new synthetic route completely of a classical chemical nature, i.e., involving no photochemical reaction, for converting steroids having the normal configuration into steroidal compounds possessing the unnatural 9 B,l0a-configuration,

In one aspect, the novel intennediatesand processes of this invention enable the preparation of 93,100:- steroids of the androstane series of the formula wherein R is, individually, selected from the-group consisting of hydroxy and lower alkanoyloxy; R is, individually, hydrogen or lower alkyl and R and R taken together, are selected from the group consisting of (17B-OH, l7a-lower alkanoic acid lactone) and oxo; R is selected from the group consisting of hydrogen, lower alkyl, hydroxy and lower alkanoyloxy; Y is selected from the group consisting of hydrogen and lower alkyl and X is a substituent in the 6- or 7- position selected from the group consisting of hydrogen, lower alkyl, lower alkylthio, lower alkanoylthio and halogen. Compounds of formula I are useful as anabolic agents.

Other 9B,l0a-androstanes, the preparation of which is enabled by the intermediates and processes of this invention, are of the formulae wherein R R Y and X have the same meaning as above. Compounds of formula III are useful as progestational agents and compounds of formula II are useful as anti-androgenic agents.

In another embodiment of this invention, the novel compounds and intermediates provided by this invention enable the preparation of 913,10a-steroids of the l7B-pregnane series of the formula GHr-Rs H O =0 ---Re rwvR'g HaC I H I i CHzOH wherein R R Y and X have the same meaning as above. Compounds of formula V are useful as salt-retaining agents, i.e., are useful in the treatment of Addisons disease.

As used herein, the term lower alkyl comprehends both straight and branched chain saturated hydrocarbon groups, such as methyl, ethyl, propyl, isopropyl and the like. Similarly, the term lower alkanoyl comprehends groups such as acetyl and the like, and the term lower alkanoyloxy comprehends groups e.g. formyloxy acetoxy and the like. In the same manner, the term lower alkenyl comprehends groups such as vinyl and the like, and the term lower alkynyl comprehends groups such as ethinyl and the like. Halogen comprehends all four halogens, i.e. iodine, bromine, chlorine and fluorine.

The expression 17B-OH, l7a-lower alkanoic acid lactone) refers to a configuration on the C-17 carbon atom illustrated as follows:

wherein W is lower alkylene, e.g. polymethylenes such as ethylene, propylene or the like.

With respect to substituents in the 6- and 7-position, preferred compounds are those having hydrogen or lower alkyl in 6- or 7-position, and those having halogen in the 7-position.

In one aspect, this invention comprises a method for the preparation of 9B, 1 Oa-androstanes of formulae MN and of 9B,l0al 7/3-pregnanes of formulae lV-V which comprises the hydrogenation of desA-androst-9-en- -ones or of desA-l7,8-pregn-9-en-5-ones to 93,10,8- desA-androstan-S-ones or 9,8,10B-desA-l7B-pregnan- 5-ones, respectively, followed by condensation with a lower alkyl vinyl ketone with methyl or ethyl vinyl ketone preferred (as well as substitutes therefor such as l-tertiary amino-3-butanone, l-tertiary amino-3- pentanone and quaternary ammonium salts thereof), l-Q-butan-3-one, 1-Q-butan-3-0ne lower alkylene ketal, 1-Q-butan-3-ol, esterified l-Q-butan-B-ol, I-Q- butan-3-ol ether, l,3-di-chlorobut-2-ene, 1,3- dichloropent2-ene, l-pentan-3-one, l-Q-pentan-3-one lower alkylene ketal, l-Q-pentan-3-ol, esterified l-Q- pentan-3-ol or l-Q-pentan-3-ol ether, which condensation yields the desired 9,8,10a-steroids. The symbol Q is bromine, chlorine or iodine, with the former two being preferred. This invention also provides a number of different methods for the preparation of said desA- 4 androst-9-en-5-one or desA-l7B-pregn-9-en-5-one startincg materials from natural steroids.

In one embodiment, a steroid of the 3-oxo-androst- 4-ene or 3-oxo-l7B-pregn-4-ene series is subjected to an oxidative ring opening of the A-ring yielding a 5- oxo-3,S-seco-A-norandrostan-3-oic acid or a 5-oxo- 3,5-seco-A-nor-l7B-pregnan-3-oic acid, which 3-oic acid can then be converted to a mixture of a IOa-desA- androstan-S-one and a lOB-desA-androstan-S-one or a mixture of a lOa-desA-l7,8-pregnan-5-one and a lOB-desA-l7B-pregnan-5-one. The conversion of the 3-oic acid to the desA-compound can be effected either by pyrolysis of a salt of said 3-oic acid or via the 'enol lactone, i.e., a 4-oxoandrost-5-en-3-one or a 4-oxo-l7B-pregn-5-en-3-one, which upon reaction with a Grignard reagent gives an aldol, which in turn can be converted into the desired desA-compound. The desA- compound can then be converted into the starting ma terial desA-androst-9-en-5-one or desA-l7B-pregn-9- en-5-one via a 2-step sequence of halogenation and dehydrohalogenation.

In another embodiment of this invention, desA- androst-9-en-5-one or desA-l7B-pregn-9-en-5-one starting materials can be prepared from ll-hydroxy steroids of the 3-oxo-androst-4-ene or 3-oxo-l 7,8- pregn-4-ene series. This can be effected in a variety of ways. In one approach, an ll-hydroxy group of a steroid of the 3-oxo-androst-4-ene or 3-oxo-17B-pregn- 4-ene series is converted into a leaving group, for example, a sulfonic acid ester or carboxylic acid ester. Oxidative ring opening of the A-ring of the thus formed 1 l-(esterified hydroxy)-containing compound yields the corresponding ll-(esterified hydroxy)-5-oxo-3,5- seco-A-norandrostan-3-oic acid or I l-(esterified hydroxy)-5-oxo-3,5-seco-A-nor-17B-pregnan-3-oic acid which upon pyrolysis of a salt of said 3-oic acid yields the desired desA-androst-9-en-5-one or desA-l 7B- pregn-9-en-5-one starting material.

A further approach involves formation of an 11- hydroxy-desAandrostan-S-one or ll-hydroxy-desA- l7B-pregnan-5-one from an I l-hydroxy steroid of the 3-oxo-androst-4-ene or 3-oxo-17B-pregn-4-ene series via an oxidative ring opening of the A-ring of said 1 1- hydroxy steroid which yields, an ll-hydroxy-S-oxo-A- nor-3,5-seco-androstan-3-oic acid 3,1l-lactone or an 1 l-hydroxy-5-oxo-3,5-seco-l 7B-pregnan-3-oic acid 3,1l-lactone which, in turn is converted into a salt of the corresponding keto acid which salt upon pyrolysis gives the l I-hydroxy-desA-androstan-5-one or I lhydroxy-desA- l 7,B-pregnan-5-one. Esterification of the I l-hydroxy moiety of the so-obtained compound with an acid moiety yields an 1 l-(esterified hydroxy)-desA- androstan-S-one or an ll-(esterified hydroxy)-desA- l7B-pregnan-5-one which upon elimination of the leaving group, i.e., the esterified hydroxy moiety) gives the desired desA-androst-9-en-5-one or desA-l7B-pregn- 9-en-5-one starting material. Though, in the above reaction sequence either the 1 la-OH or 1 lB-OH starting material steroids can be used, it is preferred to use I la- OI-l starting materials.

As will be appreciated from the above discussion, neither the specific reaction steps nor the reaction sequences of this invention involve any modification of substituents found in the l6-and/or 17-position of the starting material natural steroids. However, in order to obtain unnatural 9,8,l0a-steroids of formulae l-V, it is necessary or desirable to protect certain of the 16- and/or l7-substituents against one or more of the reaction steps involved. It is also convenient to initially protect such a substituent in the starting material natural steroid and maintain the substituent in its protected form throughout the entire reaction sequence, regenerating the desired substituent only when the steroid of formulae l-V possessing the unnatural 9,8,1011- configuration is obtained. On the other hand, it is sometimes convenient to insert a protecting group only before a certain reaction step or sequence of reaction steps. Said protecting group can then be maintained until the final reaction step or can be split off at some intermediate stage. The protecting groups can be inserted and split off by means known per se. The desirability of having protecting groups present will be further discussed below when the specific reaction steps are discussed in detail. The various substituents which are susceptible to being protected are exemplified by the .16-hydroxy group in a compound of any of formulas I-V, the 17B-hydroxy group in a compound of any of formulas l-III, the l7a-hydroxy or -oxo group in a compound of any of formulas lV-V, the 2l-hydroxy group of a compound of formula V or the 17-oxo group of a compound of formula 1.,

The 17-oxo or 20-oxo group is suitably protected by ketalization, i.e., by reaction with a lower alkanediol,

to yield a 17-lower alkylene dioxy or 20-lower alkylene dioxy compound, i.e., a l7-ketal or a 20-ketal.

The l-hydroxy, l7a-hydroxy, l7B-hydroxy or 21- hydroxy moieties can be protected by esterification and/or etherification of the hydroxy group. Any available acid which will form an ester that can be subsequently be hydrolyzed to regenerate the hydroxy group is suitable. Exemplary acids useful for this purpose are lower alkanoic acids, e.g. acetic acid, caproic acid, benzoic acid, phosphoric acid and lower alkane dicarboxylic acids, e.g. succinic acid. Also, protection for the l6a-hydroxy, l7a-hydroxy, or 2l-hydroxy substituent can be effected by forming the lower alkyl ortho ester thereof, i.e. l6a, l7aor 17a, 21 -lower alkyl ortho esters. A suitable ether protecting group is, for example, the tetrahydropyranyl ether. Others are arylmethyl ethers such as, for example, the benzyl, benzhydryl and trityl ethers, or a-lower alkoxy-lower alkyl ethers, for example, the methoxymethyl, or allylic ethers. V I

In compounds containing the dehydroxyacetone side chain at 017 (for example, compounds of formula V wherein R is hydroxy), the side chain at 017 can be protected by forming the 17,20; 20,2l-bismethylenedioxy group or by forming a l7,2l-acetal or ketal group, or by forming a 17,2l-diester. The l7,2lacetal or ketal and 17,2l-diester hinder the 20-ketone group and minimize the possibility of its participating in unwanted side reactions. On the other hand, the 17,- 20;20,2l-bis-methylenedioxy derivatives actually convert the ketone to a non-reactive derivative. When both a 16a-hydroxy and 17a-hydroxy substituent are present, these groups can be protected via formation of a l6a,l7a-acetal or ketal. The various protecting groups mentioned above can be removed by means known per se, for example, by mild acid hydrolysis.

In compounds wherein there is present neither a 17ahydroxy nor 2 1 -hydroxy substituent but there is present a 20-oxo group, the 20-oxo group can be protected via reduction to the corresponding carbinol (hydroxy) group. Thus, for example, the l7-acetyl side chain can be protected via conversion to a l7-(a-hydroxy-ethyl)- side chain. Regeneration of the l7-acetyl side chain can be simply effected via conventional oxidation means, for example, via oxidation with chromium trioxide in an organic solvent such as glacial acetic acid. Similarly in compounds containing a l7-oxo, this group can be protected by reduction to the corresponding carbinol (hydroxy) group. Thus, the l7-oxo group can be reduced to a l7B-OH, l7a-H moiety, from which, when desired, the l7-oxo moiety can be regenerated by oxidation, as described above. Furthermore, a 20- hydroxy or l7B-hydroxy group, can itself be protected by esterification, for example, with a lower alkanoic acid such as acetic acid, caproic acid, or the like;'or by etherification with moieties such as tetrahydropyranyl, benzyl, benzhydryl, trityl, allyl, or the like.

The 1604-1704 or l7a,2l-acetals and ketals above discussed can be formed by reacting 16a,17a-bis-hydroxy or l7a,2l-bis-hydroxy starting materials with an aldehyde or a ketone; preferably it is done by reacting a simple acetal or ketal, i.e., a lower alkylene glycol acetal or ketal of a suitable aldehyde or ketone, with the moieties sought to be protected. v

Suitable aldehydes and ketones include lower alkanals of at least two carbon atoms, such as paraldehyde, propanol and hexanal; di(lower alkyl)ketones, such as acetone, diethylketone, dibutylketone, methylethylketone, and methylisobutylketone; cycloalkanones, such ascyclobutanone, cyclopentanone and cyclohexanone; cycloalkyl (lower alkanals), such as cyclopentylcarboxaldehyde and cyclohexylcarboxaldehyde; cycloalkyl lower alkyl ketones, such as cyclopentyl propyl ketone, cyclohexylmethyl ethyl ketone; dicycloalkyl ketones, such as dicyclopentyl ketone, dicyclohexyl ketoneand cyclopentyl cyclohexyl ketone; cycloalkyl monocyclic aromatic ketones, such as cyclohexyl pchloropenyl ketone, cyclopentyl o-methoxyphenyl ketone, cyclopentyl o,p-dihydroxy-phenyl ketone and cyclohexyl m-tolylketone; cycloalkyl-lower alkyl monocyclic aromatic ketones, such as cyclopentylmethyl phenyl ketone; cycloalkyl monocyclic aromatic-lower alkyl ketones, such as cyclopentyl benzyl ketone and cyclohexyl phenethyl ketone; cycloalkyl-lower alkyl monocyclic aromatic-lower alkyl ketones, such as cyclopentylmethyl benzyl ketone; halo-lower alkanals, such as chloral hydrate, trifluoroacetaldehyde hemiac-, etal, and heptafluorobutanal ethyl hemiacetal; halolower alkanones, such as 1,1, l-tritlluoroacetone; monocyclic carbocyclic aromatic aldehydes, such as benzaldehyde, halobenzaldehydes (e.g. pchlorobenzaldehydc and p-fluorobcnzaldchyde), lower alkoxy-benzaldehydes (cg. o-anisaldehydc), di(lower alkoxy)benzaldehydes (e.g. veratraldehyde), hydroxybenzaldehydes (eLg. salicylaldehyde), lower alkyl benzaldehydes e.g. m-tolualdehyde and pethylbenzaldehyde), di(lower alkyl)-benzaldehydes (e.g; o-p-dimethylbenzaldehyde); monocyclic carboxylic aromatic lower alkanals, such as phenylacetaldehyde, a-phenylpropionaldehyde, B-phenylpropionaldehyde, 4-phenylbutyraldehyde, and aromatically-substituted halo, lower alkoxy, hydroxy and lower alkyl cyano derivatives thereof; monocyclic carbocyclic aromatic ketones, such as acetophenone, a,a,a-trifluoroacetophenone, propiophenone, butyrophenone, valerophenone, halophenyl lower alkyl ketones (e.g. p-chloroacetophenone and p-chloropropiophenone); (lower alkoxy) phenyl lower alkyl ketones (e.g. p-

anisyl methyl ketone); di-(lower alkoxy) phenyl lower alkyl ketones; hydroxy-phenyl lower alkyl ketones; (lower alkyl)phenyl lower alkyl ketones (e.g. methyl p-tolyl ketone); di(lower alkyl) phenyl lower alkyl ketone (o,p-xylyl methyl ketone; benzophenone, and mono-or bis-substituted halo, lower alkoxy, hydroxy and lower alkyl derivatives thereof; monocyclic carbocyclic aromatic lower alkanones, such as l-phenyl-3- butanone and l-phenyl-4-pentanone, and aromatically substituted derivatives thereof.

Especially suitable are those aldehydes or ketones which, with the 1601,170zor l7a,2l-bis-hydroxy grouping form an acetal or ketal group of the formula wherein P is individually selected from the group consisting of hydrogen and lower alkyl; Q is individually selected from the group consisting of lower alkyl and aryl; and P and Q taken together are lower alkylene. The term lower alkylene comprehends polymethylene chains such as tetramethylene and pentamethylene.

In discussing the various starting materials, intermediates and end-products of this invention, the various protecting groups discussed above will not necessarily be specifically mentioned, but it should be understood that mention of any substituent comprehends the various protected forms thereof, unless specifically mentioned to the contrary.

In one embodiment of this invention, compounds of formula I through V are prepared from 9B,l0,B-desA- androstan-S-ones or 96,10fl-desA-pregnan-S-ones of the formula HaC R -wRs H mo II VII 8 wherein R R R and X have the same meaning as above. Similarly, 9B,]Oa-androstanes of formula II can be prepared from 9B,lOB-desA-androstan-5-ones of formula VIII and 9B,lOa androstanes of formula [II from 9,8,1OB-desA-androstamS-ones of formula lX.

H w 1 i4? i H I o X VIII I Klower alkynyl MR3 H l l HaC I i wherein R R and X have the same meaning as above. Moreover, 9,8,l0a-l7/3-pregnanes of formulae IV and V can be prepared from 9,8,IOB-desApregnan-S-ones of formulae X and XI, respectively.

CHzOH H 0 41:0

butan-3-one, l-Q-butan-3-one lower alkylene ketal, l- Q-butan-3-ol, l-Q-buten-3-ol ether, esterified l-Q- butan-3-ol, l-Q-pentan-3-one, l-Q-pentan-3-one lower alkylene ketal, 1-Q-pentan-3-ol, l-Q-pentan-3-ol ether or esterified l-Q-pentan-3-ol. Q is bromo, chloro or iodo, with the former two being preferred. Methyl vinyl ketone and l-tertiary amino-S-butanone are the preferred reagents, and the former is especially preferred. Prior to the condensation it is desirable to protect the -keto group present in compounds of formulae X and XI, then it is not necessary to protect 1601,1701 or 2l-hydroxy groups which are present, but groups protecting these moieties can be retained through the condensation reaction.

The above indicated substitutes for lower alkyl vinyl ketones are compounds wherein the vinyl moiety is replaced by a moiety of the formula wherein each R is lower alkyl or taken together both Rs are lower alkylene, oxa-lower alkylene or aza-lower alkylene. Such moieties are, for example, dimethylamino, diethylamino, pyrrolidino, piperidino, morpho lino, or the like. The quaternary ammonium salts thereof are formed via the utilization of conventional quaternizing agents, for example, lower alkyl or phenyl-lower alkyl (especially benzyl) halides, mesylates or tosylates.

When a lower alkyl vinyl ketone or substitute therefor, l-Q-butan-3-one or 1-Q-pentan-3-one is used as the reaction partner for the condensation, ring closure to ring A (containing a 3-oxo moiety) of the desired 9B,]Oa-steroid of formulae l-V occurs simultaneously with the condensation. However, when 1,3- dichlorobut-Z-ene, 1,3-dichloropent-2-ene, l-Q-butan- 3-one lower alkylene ketal, l-Q-butan-B-ol, l-Q-butan- 3-ol ether, esterified. l-Q-butan-3-ol, l -Q-pentan-3-one lower alkylene ketal, l-Q-pentan-3-ol, l-Q-pentan-3-ol ether, or esterified l-Q-pentan-3-ol is used as the reaction partner a subsequent step to generate the 3-oxo moiety is required. When l-Q-butan-3-ol or l-Q- pentan-3-ol is used as the reaction partner, the 0x0 moiety can be generated by oxidation and for this purpose, it is suitable to use oxidation means known per se,

for example, chromic acid, chromium trioxide in acetic acid or the like. When esterified or etherified 1-O- butan-3-ol or esterified or etherified l-Q-pentan-3-ol is used as the reaction partner, hydrolysis of the esterified or etherified hydroxy group should be effected prior to oxidation. Suitable ester forming moieties are, for example, carboxylic acids, e.g. lower alkanoic acid such as acetic acid, benzoic acid, and the like; and hydrolysis of the reaction products obtained by reacting such l-O-butan-3-ol or l-Q-pentan-3-ol esters is suitably conducted by alkaline hydrolysis, e.g., via the use of an aqueous alkali metal hydroxide such as aqueous so dium hydroxide. Suitable ethers are, for example, lower alkyl ethers, i.e., 3-methoxy, 3-ethoxy or the like; and these are suitably hydrolyzed by acid hydrolysis, e.g. via the use of an aqueous mineral acid such as hydrochloric acid, sulfuric acid or the like. When a 1-0- butan-3-one lower alkylene ketal or a l-Q-pentan- 3-one lower alkylene ketal is used as the reaction partner, mild acid hydrolysis of the ketal moiety results in generation of the 3-oxo moiety. Finally, when 1,3-

dichlorobut-3-ene or 1,3-dichloropent-3-ene is used as the reaction partner, the 3-oxo moiety can be generated by treatment with a concentrated mineral acid, preferably a strong acid such as hydrochloric acid or sulfuric acid. It should be noted, that l,3-dichlorobut- 2-ene and l,3-dichloropent-2-ene may be used as reaction partners with compounds of formulae X and XI, but not with the 17a-lower alkyl, alkenyl oralkynyl compounds of formulae VIII-IX. As will be apparent, when a reaction partner based on butane, i.e., having a four carbon atom skeleton is utilized a compound of formulae IV wherein Y is hydrogen is obtained. Similarly, when a reaction partner based on pentane is uti lized a compound of formulae IV wherein Y is methyl is obtained.

In addition to the preparation of compounds of formulae IV from compounds of formulae VI-Xl by the use of the above mentioned reaction partners, it is also possible by the procedures of this invention to prepare compounds of formulae IV which, in the A-ring, in addition to containing an unsaturation between the 4-and S-positions also contain an unsaturation between the land 2-positions. Such 1,4-diene products corresponding to the compounds of formulae I-V can be prepared from compounds of formulae Vl-Xl by condensation of the latter with a reaction partner selected from the group consisting of ethinyl methyl ketone and ethinyl ethyl ketone (as well as substitutes therefor such as B-tertiary amino-vinyl methyl or ethyl ketone, quater nary ammonium salts thereof, and B-lower alkoxy-vinyl methyl or ethyl ketone). Condensation to prepare such a 1,4-diene product corresponding to the compounds of formulae IV is effected under the same conditions as is the condensation to prepare a compound of formulae IV. The so-obtained 1,4-dienes are useful in the same way as the correspondingly substituted 4-enecompounds of formulae IV.

The condensation is suitably effected at, below or above room temperature. For example, at the reflux temperature of the reaction medium or at ice temperature (0C.) or below. Moreover, the condensation is suitably effected in an organic medium. Preferably the solvent is a lower alkanol, such as methanol, isopropanol, tert-butanol, ethanol, or another non-ketonic organic solvent, such as an ether, e.g., dioxane, diethyl ether, diisopropyl ether, aromatic hydrocarbon, e.g., benzene, toluene, xylene, organic acid, such as acetic acid, or the like. Lower alkanols are the preferred solvents. It is suitable to catalyze the condensation, and this can be effected via use of a catalyst such as an alkali metal lower alkoxide, for example sodium ethoxide, potassium t-butoxide, sodium t-amylate, or the like, alkali metal hydroxide such as sodium, lithium or potassium hydroxide, a quaternary ammonium hydroxide, for example, a benzyl tri-lower alkyl ammonium hydroxide such as benzyl trimethyl ammonium hydroxide, para-toluene sulfonic acid, or the like.

When using a substitute for methyl or ethyl vinyl ketone, or for methyl or ethyl ethinyl ketone, the condensation should be effected under alkaline conditions. As indicated above, among such substitutes are l-tertiary amino-3-butanone, l-tertiary aminoQ-pentanone and B-tertiary amino-vinyl methyl or ethyl ketone. Preferred tertiary amino groups are dilower alkylamino groups such as dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino, or the like. Preferred quaternary ammonium salts of such tertiary amino groups are, for example, those formed from lower alkyl halides such as methyl iodide. An exemplary B-lower alkoxy vinyl methyl or ethyl ketone is B-methoxyvinyl ethyl ketone.

One aspect of this invention is the hydrogenation of desA-androst-9-en-5-ones or desA-pregn-Q-en-S-ones to 9B,lOB-desA-androstan-S-ones of formulae VII-IX or to 9B,lOB-desA-pregnan-S-ones of formulae X-XI. Thus, 9,8,lOB-desA-androstan-S-ones of formula VII can be prepared via hydrogenation of desA-androst-9- en--ones of the formulae R1 H30 R2 MR3 f mo ix R1 H3O --lower alkenyl MR3 l H HQC Lx R1 H3O 1ower alkynyl M J H H30 5 X XIV wherein R R R and X have the same meaning as above. Also, 9B,lOB-desA-pregnan-S-ones of formulae X and XI can be prepared by hydrogenation of desA-pregn-9- en-S-ones of the formulae XVI wherein R R R and X have the same meaning as above.

Prior to hydrogenation, the C-20 keto group in compounds of formulae XV and XVI or C -l7 keto group in compounds of formula XII should be protected either by conversion to the corresponding carbinol or by ketalization as described above. The hydrogenation can, however, be effected without protecting such keto groups.

Moreover, it should be noted that the hydrogenation, besides inserting a hydrogen atom in each of the 9- and l0-positions, can also simultaneously effect hydrogenation of other groups in the molecule. For example, the C-ZO-keto group can be hydrogenated to the corresponding carbinol or the G17 lower alkenyl group in compounds of formula XIII or the C-l7 lower alkynyl group in compounds of formula XIV can be hydrogenated to the corresponding C-l7-lower alkyl compounds. Compounds of formulae VIII and IX can, in turn, be prepared from compounds of formula VII wherein R and R together are oxo via reaction with a lower alkenyl or lower alkynyl Grignard reagent, with prior protection of the S-keto group, for example, by forming S-ketals without concurrent blocking of the l7-keto group. In the same manner compounds of formulae XIII and XIV can be formed from compounds of formula XII wherein R, and R taken together are oxo.

The hydrogenation of desA-androst-9-en-5-ones of formulae XII-XIV and of desA-pregn-9-en-5-ones of formulae XV-XVI is one of the main features of this invention. It is effected by catalytic hydrogenation, suitably using a precious metal catalyst. Suitable precious metal catalysts are palladium, platinum, ruthenium, and rhodium, the latter two being especially preferred. It is particularly advantageous to use rhodium, for example, rhodium on charcoal (or carbon powder, carbon black, or the like) or rhodium on alumina. In contrast to what would be expected, it has been found that such a catalytic hydrogenation of a compound of formulae XII-XVI gives a substantial yield of a compound of formulae VIXI. In fact, it has been found that such catalytic hydrogenation gives a major proportion of a compound of the formulae VI-XI. This catalytic hydrogenation is suitably effected in an inert organic solvent, for example, a lower alkanol such as methanol or ethanol, an ether such as dioxane or diglyme, a hydrocarbon such as cyclohexane, hexane, or the like. Lower alkanols are preferred solvents. Moreover, it is suitably conducted in the presence of an acidic or basic catalyst, for example, an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide or the like, or a mineral acid, for example, a hydrohalic acid, such as hydrochloric acid, or the like, or an organic acid such as a lower alkanoic acid, for example, acetic acid. The reaction can be conducted at, above or below room temperature, for example, from about 5C. to about C. However, it is preferably conducted at a temperature between about 0C. and about 35C.

As described above, the desA-androst-9-ene-5-ones or desA-17B-pregn-9-en-5-ones of formulae XII-XVI can be prepared from natural steroids by a variety of methods. Thus, in one embodiment of this invention said desA-androst-9-en-5-ones or desA-l7B-pregn-9- en-S-ones can be prepared from steroids of the 3-oxoandrost-4-ene or 3-oxo-l7B-pregn-4-ene series by a reaction sequence which involves as a first step an oxidative ring opening of ring A of the natural steroid. For this oxidative ring opening there can be used as starting materials, natural steroids of the 3-oxo-androst-4-ene or 3-oxo-l7B-pregn-4-ene series of the formula:

XVII

wherein X is a substituent in the 6-position selected from the group consisting of hydrogen, lower alkyl,

lower alkylthio and lower alkanoylthio or a substituent in the 7-position selected from the group consisting of hydrogen, lower alkyl, lower alkylthio, lower alkanoylthio and halogen, and Z represents the carbon and hydrogen atoms necessary to comxvut wherein X and Z have the same meaning as above.

The oxidative ring opening of the compound of formula XVII can be performed by a variety of methods. In a preferred embodiment it is effected by ozonolysis. The ozonolysis is suitably carried out in an organic solvent, for example, acetic acid, ethyl acetate, methanol, chloroform, methylene chloride, or the like, or a mixture of two or more of such solvents such as ethyl acetate/acetic acid, ethyl acetate/ methylene chloride, or the like. Moreover, the ozonolysis is advantageously conducted at below room temperature. Thus, it is preferably conducted at a temperature between about --70C. and about 25C. The resulting ozonides can be decomposed by conventional means, for example, by treatment with water, hydrogen peroxide in water, acetic I acid or ethyl acetate, or the like. The oxidative ring opening of acompound of formula XVII to a compound of formula XVIII can also'be effected by other oxidation means, for example, by treatment with hydrogen peroxide. It should be noted that an oxidative ring opening by either ozonolysis or by treatment with hydrogen peroxide, does not require protection of any of the substituents at C-l6 or C-I7. However, as stated above, it may be desirable to protect these substituents against some subsequent reaction in the total reaction sequence being practiced. On the other hand, the oxidative ring opening can also be effected by oxidation with chromium trioxide or via treatment with sodium periodate and potassium permanganate in potassium carbonate solution and if these oxidation means are used, it is necessary to protect any secondary hydroxy groups which might be present such as a 16,17B- or 2]- hydroxy group; preferably, for the purpose of this reaction, with non-aromatic protecting groups.

Following the oxidative ring opening of the A-ring, the so-obtained 5-oxo-3,5-seco-A-nurandrostan-B-oic acid or 5-oxo-3,5-seco-A-norpregnan-3-0ic acid of formula XVIII is converted into a mixture of a IOa-desA- androstan-5one and a IOB-desA-androstan-S-one or a mixture of a lOa-desA-pregnan-S-one and a IOB-desA- pregnan-S-one as illustrated below:

XVIII alkali metal salt of XVIII wherein in formulae XIX and XX, X and Z have the same meaning as above.

The compounds of formula XIX are l0ai-desA-. androstan-S-ones or lOa-desA-pregnan-S-ones, depending on the meaning of Z, and the compounds of formula XX are lOa-desA-androstan-S-ones or 1001- desA-pregnan-S-ones. The conversion of a compound of formula XVIII into the compounds of formula XIX and XX is effected by pyrolysis. In effecting the pyrolysis, it is desirable to convert the 3-oic acid of formula XVIII into a corresponding metal salt, for example, an alkali metal salt such as the sodium or lithium salt. This conversion to a metal salt can be effected prior to pyrolysis, e.g., by treating the acid with sodium hydroxide or in situ during the course of the pyrolysis, e.g., by fusing the 3-oic acid with a mixture of sodium acetate and potassium acetate. The pyrolysis can be conducted at atmospheric pressure or in a vacuum. One preferable embodiment is to conduct the pyrolysis in a vacuum, at a temperature from about 200C. to about 350C. in the presence of a proton acceptor, e.g., an alkali metal or alkaline earth metal salt of a weak organic acid, for

example, potassium acetate, sodium acetate, sodium phenyl-acetate, sodium bicarbonate, or the like; especially preferred is a vacuum of from about 0.001 to about 0.5 mm. Hg. Accordingly, it is advantageous to conduct the pyrolysis under alkaline conditions, i.e., at a pH greater than 7. The pyrolysis can be effected in solution or by fusion. An especially preferred method of effecting the pyrolysis is by fusion of an alkali metal salt of a weak acid, for example, an organic carboxylic acid such as a lower alkanoic acid or a phenyl-lower alkanoic acid such as phenyl-acetic acid. Another method of effecting the pyrolysis is to heat, preferably at atmospheric pressure, a solution of an alkali metal salt, such as the sodium or lithium salt, of a 3-oic acid of formula XVIII in a basic organic solvent. The basic organic solvent should, of course, be one which is in the liquid state at the temperature at which the pyrolysis is effected. Thus, the pyrolysis can be effected at a temperature up to the boiling point of the basic organic solvent being used. Suitable basic organic solvents are, for example, nitrogen containing organic solvents such as piperidine, pyridine, isoquinoline, quinoline, triethanolamine, or the like. When utilizing this approach using a basic organic solvent it is suitable to heat to temperature between about 200C. and about 300C, and preferably between about 230C. and about 260C. A preferred basic organic solvent for the pyrolysis of a salt of a compound of formula XVIII to compounds of formulae XIX and XX is quinoline. If a basic organic solvent is used which boils substantially below 200C. at atmospheric pressure, it is suitable to conduct the pyrolysis in a sealed tube or an autoclave.

In another aspect, compounds of formula XIX can be prepared from compounds of the formula I A wherein X and Z have the same meaning as above.

The compounds of formula XIX can be prepared from compounds of formula XIX A in the same manner that compounds of formula XIX are prepared from compounds of formula XVII, i.e., by oxidative ring opening of the A-ring of a compound of formula vXIX A followed by elimination of the residue of the A-ring, to

XIX B wherein X and Z have the same meaning as above,

and A is carboxy or formyl.

A compound of formula XIX B can then be converted to a compound of formula XIX. This removal of the residue of the A-ring, i.e., decarboxylation and deformylation, can be effected by heating in an acidic or basic medium. It is preferred to heat to the reflux temperature of the medium which is preferably an inert organic solvent such as a lower alkanol, e.g., ethanol, dioxane, ether or the like. The decarboxylation and deformylation yields mainly a compound of formula XIX, but also a minor yield of the corresponding 10/3- isomer of formula XX.

Compounds of formula XIX can also be formed from a compound of formula XVIII via the formation of an enol-lactone of a compound of formula XVIII, i.e. via the formation of a 4-oxo-androsb5-en-3-one or a 4-oxo-pregn-5-en-3one of the formula:

IIaC l XXI wherein X and Z have the same meaning as above,

which, upon treatment with an alkali metal hydroxide, such as potassium hydroxide, at an elevated temperature, for example, from about 200C. to about 240C, is converted to the corresponding IOa-desA-androstan- 5-one or IOa-desA-pregnan-S-one of formula XIX.

It is noted that though the pyrolysis of a compound of formula XVIII yields both the IOa-compounds of formula XX and the IOa-compounds of formula XIX, and though either of these isomers can be used in the subsequent halogenation and dehydro-halogenation steps of this reaction sequence, it is sometimes preferable to convert the IOB-compound of formula XX into the corresponding IOa-compound of formula XIX. This conversion can be effected by treating a 106- desA-androstan-S-one or IOB-desA-pregnan-S-one of formula XX with any base capable of producing a carbanion; for example, it is suitable to use an alkali metal lower alkoxide in an organic solvent such as a lower alkanol, for example, sodium ethoxide in an ethanol solution or sodium methoxide in a methanol solution.

The above-discussed conversion via the alkali metal salt and pyrolysis of compounds of formula XVIII to compounds of formulas XIX and XX can be effected without protection of any of the substituents which might be present as C-l6 or C-l7. However, if it is desired for either preceding or succeeding reaction steps of the total reaction sequence, the conversion of a compound of formula XVIII to compounds of formulas XIX and XX can be effected with protecting groups present on substituents in the C16 or C-l7 position.

As stated above, the lOa-desA-androstan-S-ones or l0a-desA-pregnan-5-ones of fonnula XIX or the 10/3- desA-androstan-S-ones of IOB-desA-pregnan-S-ones of fonnula XX can be converted via a two-step sequence of halogenation and dehydrohalogenation into the desired starting material desA-androst-9-en-5-one or dcsA-pregn-9-en-5-one of formulas XII, XV, and XVI.

In a preferred embodiment a IOa-desA-androstan- S-one or a lOa-desA-pregnan-S-one of formula XIX is subjected to the two-step sequence of halogenation and dehydrohalogenation. Halogenation of a compound of formula XIX or a compound of formula XX yields a mixture of corresponding halogenated compounds including one of the formula Hal J x XXIII wherein X and Z have the same meaning as above, and Hal is a halogen atom (preferably Br or Cl).

Dehydrohalogenation of a compound of formula XXIII then yields a desired starting material of formulas XII, XV and XVI. Keto groups except for the S-keto group, may require protection prior to the halogenation. In the case of compounds of formulas XIX and XX containing the G17 dihydroxyacetone side chain, represented in formula V wherein R is hydroxy, this protection can be effected by formation of the l7oz,20;20,2l-bismethylenedioxy derivative. In other cases wherein a O] 7 oxo or C-20 oxo group is present, protection can be effected by reduction to the corresponding carbinol either directly prior to the halogenation step or prior to some other step in the reaction sequence leading to the compounds of formulas XIX and XX.

The halogenation can be effected with halogenating agents such as bromine, sulfuryl chloride, or the like. Bromination is especially preferred. The bromination is suitably effected by treatment with bromine at room temperature or below, preferably at ice temperature or below. Suitably it is conducted in an organic medium; for example, an organic acid such as acetic acid; an ether such as an anhydrous ether, dioxane, tetrahydrofuran; a chlorinated organic solvent such as methylene chloride, chloroform, carbon tetrachloride; or the like; with the addition of hydrogen bromide as a catalyst. When effecting halogenation with sulfuryl chloride, it is suitable to use the same type of organic medium as when brominating; and suitable catalysts are, for example, acetic acid, benzoyl peroxide, or the like.

The subsequent dehydrohalogenation of a compound of formula XXIII is preferably conducted under mild dehydrohalogenation conditions; for example, by the use of an alkali metal carbonate (e.g. lithium carbonate) or an alkali metal halogenide (e.g. a lithium halide) in an organic solvent such as a di-lower alkylformamide, or with an organic base such as collidine, pyridine, or the like. The dehydrohalogenation is advantageously conducted at slightly elevated temperatures, for example, from about 50C. to about 150C, preferably from about 80C. to about 120C.

Separation of the desired product desA-androst-9- en-one or desA-pregn-9-en-5-one of formulas XII,

XV and XVI can be effected by conventional means. As indicated above the halogenation procedure may result in halogenated by-products in addition to the desired intermediate of formula XXIII. Accordingly, the

separation is preferably effected after first subjecting the reaction mixture to dehalogenating conditions in order to dehalogenate the halogenated by-products formed by the halogenation procedure, but not dehalogenated by the dehydrohalogenation. Following such dehalogenation the reaction mixture can then easily be separated by conventional means, for example, by column chromatography, to yield the desired compound of formulas XII, XV, XVI. An exemplary dehalogenation means is treatment with zinc sodium acetate in an acetic acid solution at an elevated temperature, for example, about C.

In the case of compounds of formulas XIX or XX which contain a halogen atom on a carbon atom directly adjacent to a keto group, it'is preferable to protect such a halogen atom against dehalogenation prior to subjecting the compound of formulas XIX or XX to the two step sequence of halogenation and dehydrohalogenation of this embodiment. Such a grouping, containing a halogen atom on a carbon atom directly adjacent to a keto group, is illustrated in a compound of formulas IV or V wherein R or Ra, is halogen. Thus, if l0aor IOB-desA-pregnan-S-one of formulas XIX or XX containing a 17aor 2l-halo substituent is to be subjected to the halogenation-dehydrohalogenation sequence it is desirable to first effect protection of the l7aor 2 l-halo substituent. This protection can be effected, for example, by ketalization of the 20-oxo group.

As stated above, the desired desArandrosts9-en- 5-ones or desA-pregn-9-en-5-ones starting materials can also be prepared from steroids of the 3-oxoandrost-4-ene or 3-oxo-l7B-pregn-4-ene series containing an ll-hydroxy substituent.. In one embodiment an I l-hydroxy steroid of the formula HaC I XXIV wherein X and Z have the same meaning as above, is reacted with an acid or a reactive derivative thereof to form a leaving group in the l l-position. By reactive derivative is meant, for example, a halide, e.g. a chloride, an an hydride, or the like. Though either 113- or 1 1ahydroxy starting materials can be used, it is preferable to utilize a-hydroxy compounds of formula XXIV as starting materials. Prior to the esterification reaction, it is preferable to protect hydroxy groups present in the G16, G17, or 02] position. Suitable acids for the esterification of the l l-hydroxy group, which can be used to form a leaving group in the l l-position are inorganic acids such as phosphoric acid, organic carboxylic acids such as anthraquinone B-carboxylic acid or organic sulfonic acids, for example, toluene-sulfonic acids, especially p-toluene sulfonic acid, lower alkyl-sulfonic acids such as methane-sulfonic acid and :nitrophenyl-sulfonic acids, especially p-nitrophenylsulfonic acid. Especially preferred as the leaving group in the ll-position is a lower alkylsulfonyloxy group such as the mesoxy group. However, when it is desired to react a compound of formula XXIV with a sulfonyloxy forming II Z "3G I j XXV wherein X and Z have the same meaning as above,

and LO represents the leaving group.

In the next step of this reaction sequence, the so formed ll-(esterified hydroxy)-compound of formula XXV is subjected to an oxidative ring opening of the A-ring to yield the corresponding 1 l-(esterified hydroxy)-5-oxo-3,5-seco-A-norandrostan-3-oic acid or 11- (esterified hydroxy)-5-oxo-3,S-seco-A-norpregnan-Eloic acid of the formula wherein X, Z and LO have the same meaning as above.

The oxidative ring opening of the A-ring of a compound of formula XXV to a compound of formula XXVI can be effected by ozonolysis as described above for the oxidative ring opening of the A-ring of a compound of formula XVII to a compound of formula XVIII. Pyrolysis of the so-formed compound of formula XXVI under the conditions described above for the pyrolysis of a compoundof formula XVIII to compounds of the formulas XIX and XX directly yields the desired desA-androst-9-en-5-one or desA-pregn-Q-en-S-one of formulas XII, XV, XVI. Thus, pyrolysis of a compound of formula XXVI directly results in elimination of the leaving group in the l l-position as well as a splitting off XX VI of the residue of ring A attached to the lO-position.

This procedure of starting from an 1 l-hydroxy steroid (preferably lla-hydroxy) of formula XXIV and proceeding through intermediates of formulas XXV and XXVI to compounds of formulas XII, XV, XVI, represents a particularly elegant procedure for preparing the latter compounds. An especially preferred method of effecting the pyrolysis of a salt of a 3-oic acid of formula XXVI is the method described above wherein the salt of the 3-oic acid is heated in a liquid basic organic solvent. Especially preferred solvents for the pyrolysis of a salt of a compound of formula XXVI are triethanolamine and quinoline.

As indicated in the foregoing paragraph the pyrolysis of a salt of a compound of formula XXVI involves two separate chemical attacks; one being the elimination of the l l-leaving group and the other being the splitting off of the A-ring residue. Instead of effecting these two attacks simultaneously, as described above, it is also possible to effect them sequentially by just prior to formation of the salt, effecting elimination of the leaving group of the compound of formula XXVI. This elimination yields a A -seco acid of the formula lH Z XXVIA wherein X and Z have the same meaning as above. The elimination can be effected by any conventional elimination means. It is suitably conducted under alkaline conditions in an anhydrous organic solvent. Preferably, it is effected by heating, i.e., at a temperature between about room temperature and the reflux temperature of the reaction mixture. Thus, treatment of a compound of formula XXVI with either an inorganic or organic acid or base results in the formation of the desired compound of formula XXVIA. Preferably a weak base is used, for example, a salt of a carboxylic acid (e.g. a lower alkanoic acid) with an alkali metal or an alkaline earth metal, for example, sodium acetate, potassium acetate, or the like. As indicated, the elimination is suitably conducted in an anhydrous organic solvent; suitable are solvents such as dilower alkylformamides, e.g. dimethylformamide, lower alkanoic acids, eg acetic acid, or the like. When a proton accepting solvent, such as dimethylformamide, is used, it itself can serve as the base for the purpose of this elimination reaction; i.e., if the solvent is basic then the elimination can be conducted without the addition of a separate basic material. Similarly, if the solvent is acidic, then the elimination can be conducted without the addition of a separate acidic material.

After the elimination is effected the A -seco acid product of formula XXVIA can then be converted to a salt, for example, an alkali metal salt, and the soforrned salt pyrolyzed according to the conditions described above for the pyrolysis of a compound of formula XXVI to compounds of formulas XII, XV and XVI.

After the above-described l l-leaving group elimination and A-ring residue splitting, conducted either simultaneously or sequentially, the desired desA-9-en- 5-one compounds of formulas XII, XV and XVI can be isolated by conventional means. However, it has been found particularly suitable with compounds of formulas XV and XVI to isolate by forming the disemicarbazone of the pyrolysis product and then regenerating there- 5 from the desired 5,20-dione of formulas XV or XVI, or

if the 20-oxo group has been protected, for example, by reduction to a ZO-hydroxy moiety, by forming the semicarbazone at the 5-position and then rengenerating therefrom the desired 5-one compound.

In yet another embodiment of this invention starting material 1 l-hydroxy steroids of formula XXIV can be directly subjected to an oxidative ring opening of the A-ring by ozonolysis or treatment with hydroxide peroxide, as described above for the oxidative ring opening of the A-ring of a compound of formula XVII to a compound of formula XVIII. This oxidative ring opening of the A-ring of a compound of formula XXIV yields an 1 l-hydroxy-5-oxo-3,5-seco-A-norandrostan- X xxvr wherein X and Z have the the same meaning as above.

Treatment of the 3,1l-lactone of formula XXVII with an alkali metal hydroxide such as sodium hydroxide gives the salt of the same keto acid. Without isolation, this salt can then be subjected to pyrolysis yielding a mixture of an ll-hydroxy IOa-desA-androstan-S-one and an ll-hydroxy-IOB-desA-androstan-S-one or a mixture of an ll-hydroxy-lOa-desA-pregnan-S-one and an 1l-hydroxy-lO,B-desA-pregnan-5-one, as illustrated below:

alkali metal salt wherein in formulas XXVIII and XXIX, X and Z have the same meaning as above.

This pyrolysis of an alkali metal salt derived from a compound of formula XXVII can be effected under the same conditions as described above for the pyrolysis of a compound of formula XVIII to compounds of the formulae XIX and XX. Though either the lOfi-compound of formula XXVIII or the lOa-compound of formula XXIX can be subjected to the subsequent steps of this reaction sequence, it is suitable to utilize the 103- compound of formula XXVIII. Conversion of the acompound of formula XXIX to the IOB-compound of .formula XXVIII can be effected under the same conditions as described above for the conversion of the compound of formula XX to a compound of formula XIX.

In the next step of this reaction sequence, the 11- hydroxy compound of formula XXVIII or of formula XXIX can be subjected to esterification whereby to convert the ll-hydroxy group to a leaving group in the l l-position. This esterification can be effected with the same acids or acid derivatives and in the same manner as described above for the esterification of a compound of formula XXIV to a compound of formula XXV. As in that instance, it is also preferred in the present instance to form a mesoxy leaving group in the l 1- position, though, of course, other leaving groups as described above are useful for the instant purpose. There is thus obtained a compound of the formula XXX wherein X, Z and LO have the same meanings as above particularly a compound, in accordance with this invention, having the formula:

In mow l l I H H wherein R is hydrogen, fluoro, lower alkyl, hydroxy,

lower alkanoyloxy, carboxyloweralkanoyloxy, ben- 'zoyloxy, tetrahydropyranyloxy, benzyloxy, benzhydryloxy, trityloxy, allyloxy or lower alkoxylower alkoxy; R is hydrogen, halogen, hydroxy, lower alkanoyloxy, carboxyloweralkanoyloxy, benzoyloxy, tetrahydropyranyloxy, benzyloxy, benzhydryloxy, trityloxy, allyloxy or lower alkoxy-lower alkoxy; R is hydrogen, lower alkyl, halogen, hydroxy, loweralkanoyloxy, carboxyloweralkanoyloxy, benzoyloxy, tetrahydropyranyloxy, benzyloxy, benzhydryloxy, trityloxy, allyloxy or lower alkoxy-lower alkoxy; Xis a substituent in the 6- or 7-position selected from the group consisting of hydrogen, lower alkyl, lower alkylthio, lower alkanoylthio and halogen; L0 is toluene-sulfonyloxy, lower alkylsulfonyloxy or nitrophenyl-sulfonyloxy; R is individually hydroxy, loweralltanoyloxy, carboxyloweralkanolyloxy, benzoyloxy, tetrahydropyranyloxy, benzyloxy, benzhydryloxy, trityloxy, allyloxy or lower alkoxy-lower alkoxy; and R is individually hydrogen or, taken together with R oxo or lower alkylenedioxy; or R and R taken to gether form a ketal or acetal of a lower alkanal containing at least two carbon atoms, a di(- loweralkyl)ketone, a cycloalkanone containing from four to six carbon atoms, a (cycloalkyl containing from four to six carbon atoms) lower alkanal, a (cycloalkyl containing from four to six carbon atoms) lower alkanone, a dicycloalkyl ketone containing from 11 to 13 carbon atoms, a phenyl lower alkanone or benzophenone; or R R R and R taken together form a bis-methylenedioxy; or R and R taken together form a ketal or acetal of a lower alkanal containing at least two carbon atoms; a di(loweralkyl) ketone, a cycloalkanone containing from four to six carbon atoms, a (cycloalkyl containing from four to six carbon atoms) lower alkanaLa (cycloalkyl containing from 4 to 6 carbon atoms) lower alkanone, a dicycloalkyl ketone containing from 11 to 13 carbon atoms, a phenyl lower alkanone, or benzophen'one. The leaving group can then be eliminated from the l l-position of a compound of formula XXX resulting in a direct formation of a desA-androst-9-en-5-one or a desA-pregn-9-en-5-one of formulae XII, XV, XVI. This elimination can be effected by any conventional elimination means. It is suitably conducted under alkaline conditions in an anhydrous organic solvent. Preferably, it is effected by heating, i.e. at a temperature between about room temperature and the reflux temperature of the reaction mixture. Thus, treatment of a compound of formula XXX with either an inorganic or organic base results in the formation of the desired compound of formulae XII, XV, XVI. Preferably a weak base is used, for example, a salt of a carboxylic acid (e.g. a lower alkanoic acid) with an alkali metal or an alkaline earth metal, for example, sodium acetate, potassium acetate, or the like. As indicated, the elimination is suitably conducted in an anhydrousorganic solvent; suitable are solvents such as dilower alkylformamides, e.g. dimethyl formamide, lower alkanoic acids, eg acetic acid, or the like. When a proton accepting solvent, such as dimethyl formamide,

L O pk H z HQC J It XXXA wherein X, Z and LO have the same meanings as above.

The compounds of formula XXXA can be prepared from corresponding 1 I-hydroxy compounds by esterification as described above for the preparation of compounds of formula XXV from compounds of formula XXIV.. The compounds of formula XXX can be prepared from compounds of formula XXXA in the same manner that compounds of formula XXX are prepared from compounds of formula XXV, i.e., by oxidative ring opening of the A-ring of a compound of formula XXXA followed by elimination of the residue of the A- ring to yield a compound of formula XXX. The oxidative ring opening of the compounds of formula XXXA XXXB wherein X, Z and LO have the same meaning as above.

A compound of formula XXXB can then be converted to a compound of formula XXX. This removal of the residue of the A-ring, i.e., decarboxylation, can be effected as described above for the conversion of a compound of formula XIXB to a compound of formula XIX.

The compounds of formulae I-V preparable by the methods of this invention are not only pharmaceuti-.

cally useful compounds as described above, but also are themselves useful as intermediates for other 9B,lOa-steroids; for example, compounds wherein X is hydrogen or lower alkyl can be modified so as to introduce unsaturation between C-6 and C-7. This can be effected by dehydrogenation means, for example, by halogenation followed by dehydrohalogenation or by means of 2,3-dichloro-5,6-dicyanobenzoquinone, according to known methods. Thus, for example, a 9,8,lOa-progesterone of formula IV wherein X is hydrogen or lower alkyl can be converted to a 93,100:- pregna-4,6-dien-3,20-dione.

A further embodiment of this invention comprises the preparation of 9,8,l0a-steroids of formulae I-V containing an ll-hydroxy substituent. This can be effected by utilizing an 1 lhydroxy-IOa-desA-androstan- 5-one or ll-hydroxy-lOa-desA-pregnan-S-one of formula XXIX or an ll-hydroxy-lOB-desA-androstan- 5-one or Il-hydroxy-IOB-desA-pregnan-S-one of formula XXVIII as the starting materials. It is preferred in this embodiment to use the lOB-isomers of formula XXVIII as starting materials. As a first step in this the l l-hydroxy group of the compound of formulae XXVIII or XXIX should be protected. This is suitably effected by esterification, preferably with a carboxylic acid, for example, a lower alkanoic acid such as acetic acid, benzoic acid, or the like. Conversion of the soobtained ll-esterified hydroxy compound then yields an ll-(esterified hydroxy)-desA-androst-9-en-5-one, i.e., a compound of formula XII containing an 11- esterified hydroxy moiety, or an 1 I-esterified hydroxydesA-pregn-9-en-5-one, i.e., a compound of formulae XV-XVI containing an 1 la-esterified hydroxy moiety. This conversion can be effected by halogenation followed by dehydrohalogenation, as described above for the conversion of a compound of formulae XIX or XX to a compound of formulae XII, XV or XVI. Catalytic hydrogenation of the so-obtained compound of the formula F of,

XXXI wherein X, Z and E have the same meaning as above.

This hydrogenation can be conducted in the same manner as described above for the hydrogenation of a compound of formulae XII-XVI to a compound of formulae VII, X, XI. Also, compounds of formula XXXII containing a 17-oxo moiety can be converted to a corresponding compound containing a I'm-hydroxy, 17alower alkenyl or lower alkynyl moiety by the methods described above. Also, compounds of formula XXXII can be hydrolyzed to yield corresponding ll-hydroxy compounds of formula XXXII, i.e., wherein E0 is hydroxy.

Condensation of the so-obtained compound of formula XXXll or the corresponding l7B-hydroxy, 17alower alkenyl or lower alkynyl compound, i.e., a compound of formula VI containing a free or 1 l-esterified hydroxy group, then yields the desired end-product 9/3,10a-steroid of formulae l-V containing an 1 1- hydroxy group. Such condensation can be effected as described above for the preparation of a compound of formulae l-V from a compound of formulae VI-Xl. The so-obtained 9,6,10a-steroids containing an 11- esterified hydroxy group can be hydrolyzed to the corresponding compounds containing an 1 l-hydroxy group, which latter compounds are themselves useful as intermediates, for example, the ll-hydroxy group can be oxidized by methods known per se to yield corresponding l l-oxo steroids analogous to compounds of formulas l-V.

The pharmaceutically useful compounds prepared by the methods of this invention can be administered internally, for example, orally or parenterally, with dosage adjusted to individual requirements. They can be administered in conventional pharmaceutical forms, e.g., capsules, tablets, suspensions, solutions, or the like.

The following examples are illustrative but not limitative of this invention. All temperatures are in degrees Centigrade. The Florisil adsorbent used infra is a synthetic magnesia-silica gel available from the Floridin Company, P. O. Box 989, Tallahassee, Florida (cf. p. 1590, Merck Index, 7th Edition, 1960). 100-200 mesh material was used. The moiety designated by tetrahydropyranyloxy is tetrahydro-2-pyranyloxy. When it is stated that a procedure is effected in the cold, it should be understood that it is commenced at 0C. Throughout this application when compounds of the pregnane series are referred to it should be understood that it is compounds of the l7B-pregnane series that are being referred to, unless specifically indicated to the contrary, and whether or not the compound of the pregnane series is specifically indicated as of the 17B-series Example 1 A solution of 3.2 g. of l7a-ethyltestosterone in 50 ml. methylene chloride and 25 ml. ethyl acetate was ozonized at -70 (acetone-dry ice bath) until the solution was blue in color. After oxygen was passed through, the solution was evaporated at room temperature in vacuo. The syrupy residue was then dissolved in ml. of glacial acetic acid, and after addition of 5 ml. of 30 per cent hydrogen peroxide, left for 24 hours at 0-5. Following this time, it was evaporated to dryness, dissolved in 1500 ml. ether, and extracted with 2N sodium carbonate solution. The alkaline extract was poured in ice cold hydrochloric acid. The resultant crystalline l7- a-ethyl- 1 7,8-hydroxy-5-oxo-3,5-seco-A-norandrostan- 3-oic acid was filtered, washed with water and dried. Upon being recrystallized from acetone, it melted at l- 96-l97.

Example 2 A solution of 1.5 g. of l7a-ethyl-17,8-hydroxy-5-oxo- 3,5-seco-A-norandrostan-3-oic acid in 100 ml. of meth anol was titrated with 2N sodium methoxide to the reddish color of phenolphthaleine, and then evaporated to dryness in vacuo, giving as the residue, the sodium salt of l7or-ethy1- l 7/3-hydroxy-5-oxo-3 ,5-seco-A-norandrostan-3-oic acid. 5 g. of sodium-phenylacetate was added to the residue, and the mixture pyrolyzed in vacuo O.l mm) at 285295, for 2.5 hours. The subflimate was dissolved in acetone, filtered and the filtrate concentrated in vacuo. The resultant syrupy residue Example 2a To a solution of 100 mg. of l7a-ethyl-17B-hydroxy- IOB-desA-androstan-S-one in 10 ml. of absolute ethanol was added one equivalent of sodium ethoxide dissolved in 5 ml. of absolute ethanol. This reaction mixture was maintained at room temperature overnight, then acidified with glacial acetic acid, poured in water and extracted with methylene chloride. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Thin layer chromatography showed the product to be l7a-ethy1-l 7B- hydroxy-IOa-desA-androstan-S-one. It was obtained crystalline from petroleum ether-ether and melted at 8995.

Example 3 1.13 g. of l7a-ethyl-17B-hydroxy-l0a-desA- androstan-S-one was dissolved in ml. of anhydrous ether (or 1.13 g. of lOB-isomer was dissolved in 300 ml. of anhydrous ether), and after cooling in a salt-ice bath, several drops of 30 per cent hydrobromic acid in acetic acid were added. This was followed by the drop-wise addition during 5 minutes of 0.684 g. of bromine dissolved in 2 m]. of acetic acid. This addition was synchronized with the decoloration rate of the reaction mixture. Immediately afterthis, 5 ml. of a saturated solution of sodium bisulfite and 5 ml. of 2N sodium carbonate solution were added. The mixture was then transferred into a separatory funnel, 500 ml. of ether added, shaken and separated. The ether part was washed with water, dried and evaporated. The resultant bromides were dissolved in 100 ml. of dimethylformamide, and after addition of 3 g. of lithium carbonate,

the solution was heated at 100 for 45 minutes. After cooling, it was poured into one liter of ether, washed with water, lN hydrochloric acid, 2N sodium carbonate, water, dried and evaporated. The residue was dissolved in 40 ml. of glacial acetic acid, 1.2 g. of sodium acetate and 1.2 g. of zinc powder added, and the soformed mixture heated 10 minutes at 80. It was then poured into one liter of ethylacetate and the resultant solution washed with saturated sodium bicarbonate, then with water, dried and evaporated. The residue was chromatographed on Florisil (adsorbent) column. The fraction with benzene and one-half per cent ethylacetate in benzene gave regenerated starting material. Fractions with 1 and 2 per cent ethylacetate in benzene gave 17a-ethyl-17,8-hydroxy-desA-androst-9-en-5-one, which after sublimation (140 and 0.1 mm. Hg vac uum), was obtained as a glass [01],, 36.6 (c=l, CHCl Example 4 A suspension of 262 mg. of 5 per cent rhodium-on alumina catalyst in a mixture of 26 ml. of 95 per cent ethanol and 5.25 ml. of 2N sodium hydroxide solution was pre-reduced, i.e., hydrogenated at room temperature and atmospheric pressure. To this was added a solution of 262 mg. of l7a-ethyl-l7B-hydroxy-desA- androst-9-en-5-one in 15 ml. of 95 per cent ethanol, and the mixture then hydrogenated at atmospheric pressure and room temperature. After one moleequivalent of hydrogen was absorbed, the reaction was stopped, the catalyst was separated by filtration, and the filtrate evaporated in vacuo. Glacial acetic acid (1 ml.) was added to the residue, which was then dissolved in 1 liter of ether. The cloudy solution which resulted was washed with 2N Na CO solution, then with water, dried and evaporated to dryness in vacuo.

The reaction was repeated 3 more times, and the combined products chromatographed on a Florisil (adsorbent) column. The eluates with 1 per cent ethyl acetate in benzene gave first crystalline fractions, which were followed by non-crystalline fractions. The noncrystalline fractions were dissolved in 100 ml. of methylene chloride, and after the addition of 2.5 ml. of 2 per cent CrO in 90 per cent acetic acid, stirred overnight. The excess of chromic acid was removed by washing the methylene chloride solution with ml. of 10 per cent sodium hydrogen sulfite solution, followed by washing with 2N Na CO solution and then with water. It was then dried and evaporated in vacuo. The residue was dissolved in 50 ml. of anhydrous ethanol containing 172 mg. ofsodium ethoxide, and left overnight. The next day, after addition of 0.5 ml. of glacial acetic acid, the solution was evaporated in vacuo, and the residue was taken up in 1 liter of ether. The ether solution was washed with 2N Na CO solution, then with water, dried and evaporated. The residue was chromatographed on' Florisil (adsorbent) column and gave crystalline l7a-ethyl-l 7/3-hydroxy-desA-9B, l 0,8- androstan-ob 5one identical (by thin layer chromatography) with the crystalline material obtained in the first chromatographic separation. After two recrystallizations from ether, it melted at l42l44; [011 1 165 [methanol, 0 1.245 per cent].

Example 5 To a solution of 132 mg. of l7a-ethyl-l7B-hydroxydesA-9,B,lOB-androstan-S-one in 12.5 ml. of absolute cent ethyl acetate-4O per cent heptane. The fluorescent part of the layers was extracted with ethyl acetate. The residue obtained after evaporation of ethyl acetate was first crystallized from ether-petroleum ether, then a second time from pure ether, yielding l7a-ethyl- 9B,10a-testosterone, m.p. l 3 l-l 35.

Example 6 A solution of 6.4 g. of lla-hydroxy-progesterone in 100 ml. of ethylacetate and 50 ml. of methylene chlor ide was treated with ozone at until the solution became blue in color. Oxygen was then passed through and the solution evaporated at room temperature in vacuo. The so-obtained syrupy residue was dissolved in ml. of glacial acetic acid, and after the addition of 5 ml. of 30 per cent hydrogen peroxide, left for 24 hours at 2 (in an ice box). The solution was then evaporated in vacuo, and the residue triturated with ether yielding crystals. Recrystallization from acetone yielded lla-hydroxy-3,S-seco-A-nor-pregnane-S,20- dione-3-oic acid, 3,] l-lactone, m.p. 253-25 6. [a] +l93.3 (F1, in chloroform).

Example 7 A methanolic solution of 7.5 g. of l la-hydroxy-3,5- seco-A-nor-pregnane-S,20-dione-3-oic acid 3,1 llactone was treated with one equivalent of lON sodium hydroxide solution and then evaporated to dryness. Sodium phenyl-acetate (26 g.) was added to the soobtained sodium salt and the mixture pyrolyzed at 295 for two hours in vacuo. The crude sublimate was chromatographed on a silica-gel column and eluted with 10 per cent ethylacetate in benzene. The amorphous solid 1 la-hydroxy-10a-desA-pregnane-S,20-dione was first eluted from the column. lR-spectrum in chloroform: 3620 and 3600 cm ('-Ol-l); 1706 cm (carbonyl group). NMR-spectrum in deuterochloroform: a doublet for IOa-CH at 73.5 and 80.5 c.p.s., downfield from TMS at 60 Mc/sec. Further elution of the column with 10 per cent ethylacetate in benzene yielded crystalline l la-hydroxy-1OB-desA-pregnane-S,20-dione which was recrystallized from methylene chloride-petroleum ether, m.p. l52; [a],, +84.0 (c=0.5 in absolute ethanol).

Example 8 I To a solution of 100 mg. of methanesulfonylchloride in 0.7 ml. of pyridine, there was added 100 mg. of l 10:- hydroxy-1OB-desA-pregnane-S,20-dione. The mixture was then allowed to stand overnight at 2 (in a refrigerator), then was diluted with water (100 ml.) and extracted with chloroform (3 X l50 ml.) and methylene chloride (100 ml.). The combined organic extracts were washed with water, 1N hydrochloric acid and again with water, then dried over anhydrous sodium sulfate and evaporated in vacuo. The crystalline residue srsqystal izeq. tqms her giving 1 -h d q y- Example 9 A solution of 200 mg. of lla-hydroxy-lOB-desA- pregnane-5,20-dione methanesulfonate in 50 ml. of dimethylformamide was refluxed for eight hours and then evaporated to dryness. The residue was chromatographed on a Florisil (adsorbent) column. Elution with 2 per cent ethylacetate/benzene and evaporation of the eluant yielded desA-pregn-9-ene-5,20-dione in the form of colorless needles, mp. l l ll 13. It was shown by mixed melting point to be identical with a sample of the same compound prepared as described in Example 12.

Example 10 To a solution of 20 g. of l la-hydroxy-progesterone in 150 ml. of pyridine maintained at there was added 6 ml. of methane-sulfonylchloride, and the reaction mixture allowed to stand overnight at 0. It was then diluted with a large excess of water and extracted with chloroform. The organic extracts were washed with 2N hydrochloric acid and water, then dried over anhydrous sodium sulfate and evaporated in vacuo. The solid residue was recrystallized from methanol to give lla-mesyloxy-progesterone, m.p. l59.5l60; [a] +l45.6 (c=l, chloroform).

Example 1 1 A solution of 12 g. of 1 la-mesyloxy-progesterone in 300 ml. of methylene chloride/ethyl acetate (2:1) was treated with ozone at -70 until the solution became blue in color. The excess of ozone was removed by bubbling oxygen through the reaction mixture for 5 minutes. Methylene chloride was then removed under reduced pressure, and the solution diluted with ethyl acetate to 200 ml. After addition of 12 ml. of 30 per cent aqueous hydrogen peroxide, the reaction mixture was then allowed to stand overnight at 2 i.e., in the refrigerator, then evaporated to a volume of 75 ml. and diluted with 125 ml. of benzene. The aqueous solution, obtained by extraction with 8 portions of 75 ml. 2N sodium carbonate followed by combining the aqueous extracts was acidified withcold concentrated hydrochloric acid to pH 2 and extracted with methylene chloride. This extract was dried over anhydrous sodium sulfate and evaporated in vacuo to dryness. The residue crystallized when triturated with ether-acetone mixture, yielding crude lla-mesoxy-S,20-dioxo-3,5-seco-A- nor-pregnan-3-oic acid. After recrystallization from acetone petroleum ether, m.p. l52-l53; [a],, +47.9 (c l, chloroform).

Example 12 A solution of 6 g. of l la-mesoxy-5,20-dioxo-3,5- seco-A-nor-pregnan-3oic acid in 150 ml. of methanol was mixed with a solution of 1.5 g. of sodium carbonate in 55 ml. of water. The mixture was then transferred into a 1 liter sublimation flask, and evaporated to dryness. To the thus formed sodium salt, 20 g. of sodium phenyl acetate is added, and after closing the top part of the apparatus, this mixture was pyrolyzed at 290 and 0.02 mm. for 4 hours. The product, which collects on the cold finger, was dissolved in ether and filtered. The filtrate was then evaporated to dryness. Purification of the residue by chromatography on a 40 g. silica:

gel column (benzene eluant) gave crystalline desA- pregn-9-ene-5,20-dione; m.p. l l l-l 13 (after recrystallization from ether). [01],, 568 (c 0.25 percent in methanol).

Example 131 To a solution of 1.2 g. of desA-pregn-9-ene-5,20- dione in 20 ml. of methanol maintained at 0, there was slowly added a cooled solution of 1.2 g. of sodium borohydride in 22 ml. methanol, and the resultant mixture was left for 72 hours at 0. It was then diluted with 100 ml. of water and extracted with four 100 ml. portions of chloroform. The extract was dried over anhydrous sodium sulfate and evaporated in vacuo, yielding a colorless oily product. This product was dissolved in 250 ml. of chloroform and 6 g. of manganese dioxide was added to the solution which was then stirred for 72 hours at room temperature, filtered and the filtrate evaporated to dryness in vacuo. The residue was chromatographed on a silica-gel column and the eluates with 5 per cent ethyl acetate in benzene, after concentration gave crystalline 20B-hydroxy-desA-pregn-9-en- 5-one which upon recrystallization from methylene chloride-petroleum ether formed colorless needles, mp. l22l23; [a] -33 (c 0.5, absolute ethanol). r

Example 14 A suspension of 262 mg. of 5 per cent rhodium on alumina catalyst in a mixture of 26 ml. of 95 per cent ethanol and 5.25 ml. of 2N aqueous sodium hydroxide was hydrogenated at room temperature and atomospheric pressure. To this was added a solution of 262 mg. of ZOB-hydroxy-desA-pregn-9-en-5-one in 15 ml. of 95 per cent ethanol, and the reaction mixture then hydrogenated at room temperature and atmospheric pressure. After 1 mole equivalent of hydrogen was absorbed, the reaction was stopped, and the catalyst was separated by filtration. After standing overnight the filtrate was concentrated in vacuo. To the residue was added I ml. of glacial acetic acid, and it was then dissolved in 1 liter of ether. The cloudy solution was washed with 2N aqueous sodium. carbonate solution, then with water, then dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. It yielded a colorless oil, which was chromatographed on a silicagel column using 1 per cent ethyl acetate in benzene as the elutant. First eluted with 20l3-hydroxy-l0a-desA- pregnan-S-one, m.p. l07-l08 after recrystallization from methylene chloride/petroleum ether. R.D. (in methanol); [011 -25.3, [(11 -89"; [011 274; [011 l335; [(11 -l 165.

Further elution yielded 20,8-hydroxy-9B,l0B-desA- pregnan5-one as a colorless oil. R. D. (in methanol); 1500 1400 1350 1310 2l48.

Example 15 A suspension of 262 mg. of 5 per cent rhodium on alumina catalyst in a mixture of 2 ml. of 3N aqueous hydrochloric acid and 18 ml. per cent ethanol was hydrogenated at room temperture and atmospheric pressure. A solution of 262 mg. of 20B-hydroxy-desA- pregn-9-en-5-one in 5 ml. of absolute ethanol was introduced into the hydrogenation flask, and the reaction mixture was then hydrogenated at room temperature and atmospheric pressure. After 1. mole-equivalent of hydrogen was absorbed, the reaction was stopped, the catalyst was separated by filtration, and the filtrate neutralized with 2N aqueous sodium hydroxide solution. An excess of ml. of 2N aqueous sodium hydroxide was added and the solution allowed to stand overnight. Ethanol was then removed by evaporation at reduced pressure, and after addition of 1 ml. of glacial acetic acid, it was extracted with 1 liter of ether. The extract was washed with 2N aqueous sodium carbonate solution, then with water, dried and concentrated in vacuo. It gave a colorless oil, which was chromatographed on a silica-gel column using 2 per cent ethyl acetate in benzene as the elutant. The first fractions of the eluate yielded, upon concentration, ZOB-hydroxy-lOa-desA- pregnan-S-one. From the immediately subsequent fraction, /3-hydroxy-9/3,lQB-desA-pregnan-S -one was obtained. Both products were identical with the same compounds obtained in Example 14.

Example 16 20B-Hydroxy-9B,l0a-pregn-4-en-3-one is prepared by condensation of 2OB-hydroxy-9B,10,8-desA- pregnan-S-one with methyl vinyl ketone according to the procedure of Example 5. The product melts at l76.5l78.5; [a] 143 (chloroform).

Example 17 A medium is prepared of 20 g. of Edamine enzymatic digest of lactalbumin, 3 g. of corn steep liquor and 50 g. of technical dextrose diluted to 1 liter with tap water and adjusted to a pH of 4.3 4.5. Twelve liters of this sterilized medium is inoculated with Rhizopus nigricans minus strain (A.T.C.C. 6227b) and incubated for 24 hours at 28 using a rate of aeration and stirring such that the oxygen uptake is 6.3 7 millimoles per hour per liter of Na SO according to the method of Cooper et al, Ind. Eng. Chem., 36, 504 (1944). To this medium containing a 24 hour growth of Rhizopus nigricans minus strain, 6 g. of l7a-acetoxy-progesterone in 150 ml. of acetone is added. The resultant suspension of the steroid in the culture is incubated under the same conditions of temperature and aeration foran additional 24 hour period after which the beer and mycelium are extracted. The mycelium is then filtered, washed twice, each time with a volume of acetone approximately equal in volume to the mycelium, extracted twice, each time with a volume of methylene chloride approximately equal to the volume of the mycelium. The acetone and methylene chloride extracts including solvent are then added to the beer filtrate. The mixed extracts and beer filtrate are then extracted successively with 2 portions of methylene chloride, each portion being one-half the volume of the mixed extracts and beer filtrate, and then with 2 portions of methylene chloride, each portion being one-fourth the volume of the mixed extracts and beer filtrate. The combined methylene chloride extracts are then washed with 2 portions of a 2 per cent aqueous solution of sodium bicarbonate, each portion being one-tenth the volume of the combined methylene chloride extracts. The methylene chloride extracts are then dried with about 3 5 g. of anhydrous sodium sulfate per liter of solvent, and then filtered. The solvent is then removed from the filtrate by distillation, and the residue is dissolved in a minimum of methylene chloride, filtered and the solvent evaporated from the filtrate. The resulting crystals are then dried and washed five times, each time with a 5 ml. portion of ether per gram of crystal. The crystals are then recrystallized from ether giving l7a-acetoxyl la-hydroxy-progesterone. lz-acetoxy-l la-mesoxyprogesterone is prepared by treatment of 17a-acetoxylla-hydroxy-progesterone with methanesulfonyl chloride, according to the procedure of Example 10.

Example 18 l7a-Acetoxy-5,20-dioxo-l lwmesoxy-A-nor-f'a ,5- seco-pregnan-3-oic acid is prepared by ozonolysis of l7a-acetoxy-1 1a-mesoxy-progesterone, according to the procedure of Example 11.

Example 19 17a-Acetoxy-desA-pregn-9-ene-5,20-dione is prepared from l7a-acetoxy-5 ,20-dioxo-l la-mesoxy-A- nor-3,5-seco-pregnan-3-oic acid by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 12.

Example 20 17a-Acetoxy-20B-hydroxy-desA-pregn-9-en-5-one is prepared from 17a-acetoxy-desA-pregn-9-en-5,20- dione by reduction and reoxidation according to the procedure of Example 13.

Example 2] 17a-Acetoxy-2OB-hydroxy-9B, lOB-desApregnan- 5-one is prepared from l7a-acetoxy-2OB-hydroxydesA-pregn-9-en-5-one by hydrogenation under acidic conditions of the presence of a rhodium catalyst according to the procedure of Example 15.

Example 22 1 7a-Acetoxy-20,8'hydroxy-9,B,10a-pregn-4-en-3-one is prepared by condensing methyl vinyl ketone with 17- a-acetoxy-ZOB-hydroxy-9B, l OB-desA-pregnan-S-one according to the procedure of Example 5 except instead of conducting the condensation in absolute ethanol and catalyzing it with sodium ethoxide, the condensation is conducted in acetic acid and is catalyzed with p-toluene sulfonic acid.

Example 23 20B-Hydroxy-4-methyl-9B,lOa-pregn-4-en-3-one is prepared by condensing 2OB-hydroxy-9B,l0B-desA- pregnan-S-one and ethyl vinyl ketone according to the procedure of Example 5.

Example 24 17B-Hydroxy-5-oxo-3 ,5-seco-A-androstan-3-oic acid is prepared by ozonolysis of testosterone according to the procedure of Example 1.

Example 25 17B-Hydroxy-lOa-desA-androstan-S-one and 1 7B- hydroxy-lOB-desA-androstan-S-one are prepared from 17B-hydroxy-5-oxo-3,5-seco-A-norandrostan-3-oic acid by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 2.

Example 26 17,8-Hydroxy-desA-androst-9-en-5-one is prepared from l7,8-hydroxy-IOa-desA-androstan-S-one by bromination followed by dehydrobromination, according to the procedure of Example 3.

Example 26a Example 27 A solution of 236 mg. of 17B-hydroxy-desA-androst- 6-en-5-one in 40 ml. 95 per cent ethanol and 5.25 ml. 2N aqueous sodium hydroxide solution was hydrogenated with one mole equivalent of hydrogen over 236 mg. of prereduced 5 per cent rhodium on alumina catalyst. After separation of catalyst, the solution was concentrated in vacuo to dryness, and the residue taken up in 1 liter of ether. The ether solution was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. From the residue 178- hydroxy-9,B,lOB-desA-androstan-S-one was obtained by crystallization. M.p. 144.5-145; [a],, 22 (c 0.103; dioxane). The 17,8-acetate, i.e., l7B-acetoxy- 9B,10B-desA-androstan 5-one, is obtained by acetylation oftestosterone followed by ozonolysis, pyrolysis, bromination and dehydrobromination, and reduction according to the methods of Examples 24, 25, 26 and 27 respectively, and melts at 1 18- 1 19; [M -28 (c 0.103; dioxane).

Example 28 A solution of 238 mg. of l7B-hydroxy-9B,l0B-desA- androstan-5-one, 1 ml. of ethylene glycol and catalytic, amount of p-toluene sulfonic acid in 100 ml. of anhydrous benzene was slowly distilled until no more water was coming over. The solution was then concentrated in vacuo to a small volume, and l7B-hydroxy-9/3,1OB- desA-androstan-S-one S-ethylene ketal was obtained from the residue by crystallization. M.p. l l51 16; [a],, 9 (c 0.0987; dioxane).

Example 29 To a solution of 282 mg. of 17B-hydroxy:9,8,l0,8- desA-androstan-5-one S-ethylene ketal in 50 ml. of methylene chloride was added 1 equivalent of 2 per cent chromic acid in pyridine, and the reaction mixture then stirred overnight. The reaction mixture was then washed with 10 per cent aqueous sodium hydrogen sulfite, 2N aqueous sodium carbonate, water, then dried over anhydrous sodium sulfate and concentrated in vacuo to dryness. Crystallization of the residue gave 9- ,B, l B-desAandrostane-5, 1 7-dione -monoethylene ketal. Splitting of the ketal in acetone solution in the presence of a catalytic amount of p-toluene sulfonic acid gives 913,1OB-desA-androstane-S,l7-dione which melts, after recrystallization from cyclohexane, at 775 -78"; [a] -l-55, (c 0.107; dioxane).

Example 30 To a preformed solution of one mole equivalent of prop-1 '-inyl lithium in 100 ml. of anhydrous liquid ammonia was added tetrahydrofuran solution of 200 mg. of 9B, 1 OB-desA-androstane-S l 7-dione 5-monoethylene ketal, and the reaction mixture stirred for 2 hours. After addition of onegram of ammonium chloride, cooling was discontinued, and the reaction mixture allowed to evaporate. The residue was extracted with methylene chloride, the extract was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in 20 ml. of acetone and the catalytic amount of p-toluenesulfonic acid added, and the solution was refluxed for two hours, then poured in water and extracted in methylene chloride. The methylene chloride extract was washed with water, then dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. Crystallization of the residue gave 17a- (prop-l '-inyl)- l 7B-hydroxy-9B, 1 OB-desA-androstan- 5-one.

Example 31 Example 32 To a stirred solution of one mole equivalent of 2-methyl-prop-2-enyl magnesium bromide in ml. of ether at room temperature was added dropwise a solution of 280 mg. of 9B,IOB-desA-androstane-S, 1 7 dione and S-mono-ethylene ketal :in 100 ml. of tetrahydrofuran. The reaction mixture was refluxed for one hour. After cooling in an ice-salt bath, a saturated solution of sodium sulfate was slowly added to decompose the Grignard complex. This was followed by addition of anhydrous sodium sulfate. The solution was separated by filtration and concentrated in vacuo to dryness. The solution of the residue and of a catalytic amount of ptoluene'sulfonic acid in 20 ml. of acetone was refluxed for two hours, then poured in water and extracted in methylene chloride. Methylene chloride extract was washed with water, dried over anhydrous sodiumsulfate and evaporated to dryness. From the residue 17a-(2- methyl-prop-2'-enyl l 7B-hydroxy-9B, 1 OB-desA- androstan-S-one was obtained.

Example 33.

l'Za-( 2 -methyl-prop-2-enyl l 7B-hydroxy-9B, 1 0aandrost-4-en-3-one is prepared from l7a-(2'-methylprop-2'-eny1)- l 7,8-hydroxy-9B, 1 OB-desA-androstan- S-one by condensation of the latter with methyl vinyl ketone according to the procedure of Example 5. The

product melts at l06108.

Example 34 Example 35 l 6a-Acetoxy-20-ethylenedioxylOa-desA-pregnan- 5-one and l 6a-acetoxy-20-ethylenedioxyl OB-desA- pregnan-S-one are prepared from l6a-acetoxy-20- ethylenedioxy-5-oxo-3,5 seco-A-norpregnan-3-oic acid by conversion of the latter to itssodium salt followed by pyrolysis (according to the procedure of Example 2) and reacetylation with acetic anhydride and pyridine.

Example 36 l6a-Acetoxy-20-ethylenedioxy-desA-pregn-9-en- 5-one is prepared from l6a-acetoxy-20-ethylenedioxy- IOa-desA-pregnan-S-one by bromination followed by dehydrobromination, according to the procedure of Example 3.

Example 37 l6oz-Acetoxy-20-ethylenedioxy-9B, lOB-desA- pregnan-S-one is prepared from l6a-acetoxy-20- ethylenedioxy-desA-pregn-9-en-5-one by hydrogenation under basic conditions in the presence of a rhodium catalyst, according to the procedure of Example 14.

Example 38 1 604-Hydroxy-ZO-ethylenedioxy-9B, la-pregn-4-en- 3-one is prepared by l6a-acetoxy-20-ethylenedioxydesA-9B,lOB-pregnan-S-one with methyl vinyl ketone according to the procedure of Example 5.

Example 39 Example 40 l6a-Methyl-20-ethylenedioxyl Oa-desA-pregnan- -one and la-methyl--ethylenedioxyl OB-desA- pregnan-S-one are prepared from l6a-methyl-20- ethylenedioxy-5-oxo-3,5-seco-A-norpregnan-3-oic acid by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 2.

Example 41 l6a-Methyl-20-ethylenedioxy-desA-pregn-9-en- 5-one is prepared from l6a-methyl-20-ethylenedioxylOu-desA-pregnan-S-one by brominationfollowed by dehydrobromination, according to the procedure of Example 3.

- Example 42 l6a-Methyl-20-ethylenedioxy-9B, l OB-desA- pregnan-S-one is prepared from l6a-methyl-20- ethylenedioxy-desA-pregn-9-en-5-0ne by hydrogenation under basic conditions in the presence of a rhodium catalyst, according to the procedure of Example 14.

Example 43 l6a-Methyl-20-ethylenedioxy-9B, l Oa-pregn-4-en- 3-one is prepared by condensing l6a-methyl-20- ethylenedioxy-9,B, l OB-desA-pregnan-S-one with methyl vinyl ketone, according to the procedure of Example 5.

Example 44 2 l -Acetoxyl la-hydroxy-ZO-ethylenedioxy-pregn-4- en-3-one is prepared by microbiological treatment of 2- -acetoxy-2O-ethylene-dioxy-pregn-4-en-3-one, according to the procedure of Example 17. 2 l-Acetoxyl la-mesoxy-ZO-ethylenedioxy-pregn-4-en-3-one is prepared by treatment of 2l-acetoxy-l la-hydroxy-ZO- ethylenedioxy-pregn-4-ene-3-one with methane sulfonyl chloride, according to the procedure of Example 10.

Example 45 2 l -Acetoxy-l loz-mesoxy-20-ethylenedioxy-5-oxo- 3,5-seco-A-norpregnan-3-oic acid is prepared by ozonolysis of 2 l-acetoxy-l loz-mesoxy-ZO-ethylenedioxypregn-4-en-3-one, according to the procedure of Example 11.

Example 46 2 l -Acetoxy-20-ethylenedioxy-desA-pregn-9-en- 5-one is prepared from 21-acetoxy-20-ethylenedioxy- 1 la-mesoxy-3,5-seco-A-norpregnan-3-oic acid by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 12, except that the crude product is reacetylated by treatment with acetic anhydride/pyridine prior to its being worked-up.

Example 47 2 l -Acetoxy-20-ethylenedioxy-9B, l 0,13-desA- pregnan-S-one is prepared from 2l-acetoxy-20- ethylenedioxy-desA-pregn-9-en-5-one by hydrogenation under acidic conditions in the presence of a rhodium catalyst, according to the procedure of Example 15.

Example 48 21-Hydroxy-20-ethylenedioxy-9B,l0a-pregn-4-en- 3-one is prepared from 2l-acetoxy-20-ethylenedioxy- 9,8,IOB-desA-pregnan-S-one by condensing the latter with methylvinyl ketone, according to the procedure of Example 22.

Example 49 l la-Mesoxy- 1 6a, 1 7a-isopropylidenedioxyprogesterone is prepared by treatment of l la-hydroxy- 1 601,1 701-isopropylidenedioxy-progesterone with methane sulfonyl chloride, according to the procedure of Example 10.

Example 50 5 ,ZO-dioxo-l la-mesoxyl 6a,17aisopropylidenedioxy-3,5-seco-A-norpregnan-3-oic acid is prepared by ozonolysis of lla-mesoxy-l6a,l7aisopropylidenedioxy-progesterone, according to the procedure of Example 1 1.

Example 51 16a, 1 7a-isopropylidenedioxy-desA-pregn-9-en- 5,20-dione is prepared from 5,20-dioxo-l la-mesoxy- 16a, 1 7a-isopropylidenedioxy-3,5-seco-A-norpregnan- 3-oic acid by conversion of the latter to its sodium salt, followed by pyrolysis according to the procedure of Example l2.

Example 52 Example 53 B-Hydroxy- 1 601,1 7a-isopropylidenedioxy-9B, l 0,8- dsA-pregnan-S-one is prepared from ZOB-hydroxy- 1601,] 7a-isopropylidenedioxy-desA-pregn-9en-5-one by hydrogenation according to the procedure of Example 14.

Example 54 2OB-Hydroxy- 1 6a, 1 7a-isopropylidenedioxy-9B,10apregn-4-en-3-one is prepared by condensing methyl vinyl ketone with 20/3-hydroxy-l6a,17aisopropylidenedioxy-desA-9B, l 0,B-pregnan-5-0ne according to the procedure of Example 5.

Example 55 7a, 1 7a-dimethyll 7B-hydroxy-5-oxo-3,5-seco-A- norandrostan-3-oic acid is prepared from 7a,]7a-dimethyl-testosterone by ozonolysis of the latter, according to the procedure of Example 1.

Example 56 Example 57 70:, l .z'la-dimethyl- 1 7,B-hydroxy-desA-androst-9-en- 5-one is prepared from 7a,l7a-dimethyl,-l 7,8-hydroxylOa-desA-androstan-S-one by bromination followed by dehydrobromination, according to the procedure of Example 3.

Example 58 701,17a-dimethyl-l7B-hydroxy'desA-9B,l0B- androstan-5-one is prepared from 7oz,17a-dimethyll7/3-hydroxy-desA-androst-9-en-5one by hydrogenation in the presence of a rhodium catalyst, according to the procedure of Example 4.

Example 59 7a, 1 7a-dimethyl-9B, l Oar-testosterone is prepared from 701,1 7oz-dimethyl-17B-hydroxy-desA-9B,l0flandrostan-S-one by condensing the latter with methyl vinyl ketone, according to the procedure of Example 5.

Example 60 l la-Mesoxy- 1 7a-methyl-progesterone is prepared from 1la-hydroxy-l7a-methyl-progesterone by treatment of the latter with methane sulfonyl chloride, according to the procedure of Example 10.

' Example 61 l 1 a-mesoxyl 7a-methyl-5,20-dioxo-3 ,5 seco-A-normethyl-progesterone by ozonolysis of the latter, ac cording to the procedure of Example 1 1.

Example 62 l7a-methyl-desA-pregn-9-ene-.5,20-dione is prepared from 1 la-mesoxy-17a-methyl-5,20-dioxo-3,5-

seco-A-norpregnan-3-oic acid by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 12.

. Example 63 20B-Hydroxy-1 7a-methyl-desA-pregn-9en-5-one is prepared from l7a-methyl-desApregn-9en-5,20- dione according to the procedure of Example 13.

Example 64 ZOB-Hydroxy- 1 7a-methyl-9B, 1 OB-desA-pregnan- S-one is prepared from. l7a-methyI-ZOB-hydroxy-desA- pregnan-9-ene-5-one according to the procedure of Example 15. i r

Example 65 ZOB-Hydroxy-17a-methyl-9B,l0apregn-4-en-3-one is prepared by condensing 17a-methyl-20B-hydroxy- 9,8,10B-desA-pregnan-5-one with methyl vinyl ketone,

according to the procedure of Example 4.

pregnan-3-oic acid is prepared from lla-mesoxy-17a- Example 66' A solution of 12.8 g. of l7a-methyltestosterone in 200 ml. of methylenechloride and 100 m1. of ethyl acetate was ozonized for 1 hour and 5 minutes at (acetone-dry ice bath) until a blue color developed. After oxygen was bubbled through, the solution was then concentrated at room temperature in vacuo. The residue was dissolved in 400ml. of acetic acid, and after addition of 30 ml. of .30 percent hydrogen peroxide, the solution was left overnight at 0. It was then evaporated to dryness in vacuo, the residue taken up in ether, and the ether solution extracted with 2N AQUE- OUS SODIUM CARBONATE 12 X 50 ml. The combined carbonate extracts were cooled in ice, and. aciditied with concentrated hydrochloric acid. The aqueous suspension of precipitated organic acid was extracted with methylene chloride, this extract was washed with water, dried over anhydrous sodium sulfate and evaporated giving as a colorless crystalline material 175- hydroxyl 7a-methyl-5-oxo-3,5-seco-A-nor-androstan- 3-oic acid. After recrystallization from acetonehexane, it melted at l-l97, [011 9.8 (c 1.0 in chloroform).

Example 67 A solution of 10 g. of l7B hydroxy-l7a-methyl-5- oxo-3,5-seco-A-nor-androstan-3-oic acid in 250 ml. of methanol was made alkaline to phenolphthalein with sodium ethoxide, and evaporated to dryness. The residual powdery sodium salt was mixed well with 32 g. of sodium phenylacetate and 40 g. of neutral alumina (Woelm, Grade I), and the mixture heated at 290 in vacuo for 4 hours. After cooling to room temperature, a large excess of water was added, and the resultant suspension extracted with 2 liters of ether. The ether extract was washed with water, aqueous 2N sodium carbonate solution, and again with water, dried and evaporated. This gave a sirupy residue, which bythin layer chromatograrns and infrared spectra consisted of 1 7B-hydroxy- 1 7a-methyl- 1 Oa-desA-androstan-S-one 

2. The compound of claim 1 having the formula:
 3. The compound of claim 2 wherein said compound is 11 Alpha -hydroxy-10 Beta -desA-pregnane-5,20-dione.
 4. The compound of claim 2 wherein said compound is a 11 Alpha -(toluene-sulfonyloxy, loweralkyl-sulfonyloxy or nitrophenyl-sulfonyloxy)-desA-pregnane-5,20-dione.
 5. A compound as in claim 4 which is 11 Alpha -hydroxy-10 Beta -desA-pregnane-5,20-dione methanesulfonate.
 6. The compound of claim 1 having the formula: 